Serum Amyloid a Exacerbates Acute Vascular Events by Activation of the NLRP3 Inflammasome

Serum Amyloid A (SAA) is an HDL associated acute phase protein that can increase hundreds of fold during acute cardiovascular events. The increase SAA levels predicts early mortality in coronary syndromes. We will present data that SAA is more than a marker but a mediator of acute vascular events. SAA possess the ability to induce cytokines, promote phagocyte chemotaxis, and up-regulate genes involved in extracellular matrix remodeling. Under homeostatic conditions SAA is innocuous, partially due to its association with HDL. We propose acute vascular injury unmasks SAA’s potential to inappropriately amplify inflammatory responses and enhance tissue damage. The relevance of this was tested in SAA deficient mice utilizing an Angiotensin II model of abdominal aortic aneurysms. The deficiency of SAA reduced inflammation and abrogated subsequent aneurysm formation typical of this model. We determined that SAA induces IL-1β and NLRP3 expression, as well as IL-1β secretion, in J774 macrophage-like cells, consistent with priming and activation of the NLRP3 inflammasome. We determined that reduced AngII-induced AAA in SAA-deficient mice is accompanied by significant reductions in plasma IL-1β, indicating inflammasome activation in AngII-infused mice is dependent on SAA. These mechanisms may be relevant in the unstable atherosclerotic plaque particularly when SAA levels are increased. More frequent measurement of human SAA in acute vascular syndromes should be explored.